ENESTnext Final Results: Deep Molecular Response (MR) with Nilotinib (NIL) in Patients (pts) with Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase (CML-CP)

Background: Regular monitoring of MR by real-time quantitative polymerase chain reaction (RQ-PCR) on the International Scale (IS) is critical for proper management of pts with CML-CP, and achievement of deep MR is a key criterion for enrollment in treatment-free remission studies. In addition, newer techniques have been developed for evaluating residual disease below the level of detection of conventional RQ-PCR. The BCR-ABL1 tyrosine kinase inhibitor NIL elicits higher rates of deep MR than imatinib (IM) in pts with newly diagnosed CML-CP. Prior results from ENESTnext in this pt population demonstrated rapid achievement of deep MR by conventional RQ-PCR and further reductions in BCR-ABL1 transcript levels using a microfluidic digital PCR platform in pts who achieved confirmed MR^4.5 (BCR-ABL1^IS ≤ 0.0032%) with NIL. Final results are presented here.

Methods: ENESTnext (NCT01227577) was a single-arm, open-label, multicenter study in adult pts with Philadelphia-chromosome-positive CML-CP (diagnosed within ≤ 6 months of enrollment) treated with NIL 300 mg twice daily (BID) for up to 2 years. The primary endpoint was the rate of confirmed (≥ 2 samples taken 3 months apart) MR^4.5 with up to 2 years of NIL therapy. Secondary endpoints included the rate of major MR (MMR; BCR-ABL1^IS ≤ 0.1%). RQ-PCR evaluation of peripheral blood samples was performed monthly for the first 3 months and every 3 months thereafter by a central laboratory and according to the IS. In an exploratory analysis, samples from pts with confirmed MR^4.5 (limit of detection of the RQ-PCR assay used) were also evaluated using the Fluidigm digital PCR platform (detection limit is approximately 1 positive cell in 1,000,000 negative cells), which is > 1 log more sensitive than conventional RQ-PCR. Samples were analyzed by both digital PCR and RQ-PCR for each pt upon achievement of confirmed MR^4.5.

Results: A total of 128 pts were enrolled (median age, 56.5 years; male, n = 64 [50.0%]; Caucasian, n = 103 [80.5%]), and 93 pts (72.7%) completed the study per protocol. With up to 2 years of treatment, 94 pts (73.4%) achieved MMR and 34 pts (26.6%) achieved confirmed MR^4.5 (Table). Overall, 13 of 94 pts (13.8%) lost MMR and 6 of 34 pts (17.6%) lost MR^4.5; among the pts who gained and lost MMR (n = 13) or MR^4.5 (n = 6), the mean duration of response was 4.9 and 8.0 months, respectively. All pts who achieved MR^4.5 had BCR-ABL1^IS ≤ 10% at 3 months. Digital PCR analysis was performed on 195 samples from 33 pts with confirmed MR^4.5 by RQ-PCR. Results of digital PCR detection of BCR-ABL1 transcripts in the first and last time point samples from each pt are shown in the Table; among pts for whom both the first and last time point samples showed detectable BCR-ABL1 transcripts by digital PCR, levels decreased over time with continued NIL therapy. The most common (≥ 4 pts) all-cause grade 3/4 adverse events were increased lipase (n = 16), thrombocytopenia (n = 11), neutropenia (n = 8), hypophosphatemia (n = 5), and nausea (n = 5). The most common cardiac disorders were palpitations (6.3%) and atrial fibrillation, myocardial infarction, and tachycardia (2.3% each). Ischemic cardiovascular events included myocardial infarction (2.3%) and cerebrovascular accident and transient ischemic attack (0.8% each).

Conclusions: Rapid achievement of MR^4.5 was observed in pts with newly diagnosed CML-CP receiving frontline NIL 300 mg BID in ENESTnext; rates of MR were also consistent with those from the ENESTnd study of frontline IM vs NIL with 2 years of follow-up. In ENESTnext, 39% of samples analyzed by digital PCR had detectable levels of BCR-ABL1 transcripts that were not detectable by conventional RQ-PCR, suggesting the potential for detection of even deeper levels of MR using this novel method.

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